P-35 Zanzalintinib (XL092) in combination with atezolizumab for previously treated metastatic colorectal cancer

Metastatic colorectal cancer (mCRC) is associated with poor prognosis, and patients who have progressed on first- and second-line chemotherapy have limited treatment options. Regorafenib and trifluridine-tipiracil are approved in third- or later-line settings, but survival benefit is small. Immune checkpoint inhibitor (ICI) therapy with nivolumab ± ipilimumab or single-agent pembrolizumab is approved in patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) mCRC, which constitutes a small subgroup (∼5%) of the overall patient population. As the vast majority of patients are microsatellite stable or mismatch repair proficient and, therefore, unlikely to respond to ICI alone, there remains an unmet need for effective treatment options for these patients. Phase 1/2 studies evaluating cabozantinib (an inhibitor of MET, AXL, and VEGFR2) in combination with atezolizumab and durvalumab have demonstrated encouraging clinical activity (Abrams TA, et al. ASCO GI 2022:Abs 121; Saeed A, et al. ASCO GI 2022:Abs 135). Zanzalintinib (XL092) is a tyrosine kinase inhibitor that targets MET, VEGFR2, and the TAM kinases AXL and MER; these proteins are implicated in tumor growth, metastasis, angiogenesis, and immunosuppression of the tumor microenvironment. Zanzalintinib also displays immunomodulatory properties that may promote an immunopermissive tumor microenvironment and enhance response to ICIs. Results from a phase 1 dose-escalation study of zanzalintinib alone or in combination with atezolizumab in patients with locally advanced or metastatic solid tumors (including mCRC) showed a manageable safety profile. Zanzalintinib has a half-life of 16–22 hours, supporting a once-daily dosing regimen (Sharma MR, et al. ESMO 2022:Abs 481P). The phase 3 STELLAR-303 study (NCT05425940) is evaluating the efficacy and safety of zanzalintinib in combination with atezolizumab versus regorafenib in patients with microsatellite stable or microsatellite instability-low mCRC who have progressed after or are intolerant to standard of care (SOC) therapy. Trial design:STELLAR-303 is a global, randomized, open-label, phase 3 study. Eligible patients are aged ≥18 years with non-MSI-H/dMMR mCRC (determined by tissue-based analysis) that is measurable per RECIST v1.1 by investigator and have an ECOG performance status of 0–1 and adequate organ function. Patients must have progressed during/after or be intolerant to SOC therapies for mCRC; prior regorafenib, trifluridine-tipiracil, or anti–PD-L1/PD-1 ICIs are not allowed. Patients are randomized 1:1 to zanzalintinib + atezolizumab or to regorafenib. Zanzalintinib is administered orally once a day. Enrollment of 600 patients (including RAS wild-type and RAS mutant) is planned. The primary endpoint is duration of overall survival and secondary endpoints include progression-free survival, objective response rate, and duration of response (all per RECIST v1.1 by investigator), as well as safety and tolerability. Enrollment is ongoing in 16 countries, located in North America, Europe, and Asia-Pacific regions. NCT05425940. Editorial assistance was provided by Fishawack Communications Inc., part of Fishawack Health, and funded by Exelixis, Inc. Exelixis, Inc.